Recent studies suggest that the capacity for the brain to use multiple substrates such as glutamine, acetoacetate, 3-hydroxybutyrate as well as glucose for energy and structural components is critical for the normal development of mammalian nervous tissue. As a result, a new series of hypotheses and research strategies related to neurobiological mechanisms have been developed. The present group of studies represents a multi-disciplinary program directed toward defining the factors that regulate the cellular priorities for the use of different substrates by specific cell types of the nervous system. Specific emphasis will be placed on the changes that occur during nearly development. In one project we will determine the roles of hormones and metabolic intermediates in regulating the transport and utilization of ketone bodies and glucose in various brain cell types. A second project will determine the role of glutamine as an energy source in brain under different developmental, hormonal and dietary conditions and the role of multiple carbon sources as precursors for this amino acid. An important aim of this project is to determine the role of glutamine metabolism and CO2 fixation in replenishing key TCA cycle intermediates in neurons, and astrocytes. A third project will continue to determine the metabolic events and factors regulating substrate use during growth and regeneration of adrenergic neurons using the rat superior cervical ganglion as a model. In the fourth project we will determine the metabolic fate of ketone bodies and glucose in individual cell types in brain. The progress made in this project in developing and refining the methodology for obtaining homogenous cell populations from brain enables us to determine the in vivo fate of metabolites under the same hormonal conditions used for the in vitro studies in project one. The aim of a fifth project is to define the mechanism whereby serum causes an alteraton in the metabolic fate of glucose in nerve cells and to isolate and characterize the factor that is responsible for this action. Also included in project V are a series of investigations to characterize the effect of thyroid hormone on neurotransmitter enzymes. The result of this integrated multi-disciplinary proposal should provide a basis for understanding some of the complex metabolic alterations underlying mental retardation and they should be also helpful in the development of guidelines for clinical management of infants with developmental disabilities.